Despite regeneration, extensive peripheral nerve injuries can result in the effective paralysis of the entire limb or distal portions of the limb. Refinement of microsurgical techniques involving the introduction of the surgical microscope and microsutures has increased the accuracy of this mechanical process, however only 10% of adults will recover normal nerve function using state-of-the-art techniques. The major key to recovery of function following nerve lesions in the peripheral nervous system is the accurate regeneration of axons to their original target end-organs. Unfortunately, when a mixed peripheral nerve is repaired, regenerating motor axons are often misrouted to a non-muscle target which leads to poor functional recovery and rehabilitation. During the course of our recent studies we have made an unexpected discovery; information from a denervated muscle is apparently rapidly conveyed to the proximal nerve lesion site and influences the subsequent accuracy of motor neuron regeneration. We have also made the surprising observation that the application of a low voltage direct current field in vivo enhances the uptake of compounds injected into distal peripheral nerve, and that such stimulation also results in the accumulation of the applied compounds at a more proximal nerve repair site (a phenomenon that we have termed Whole-Nerve Electrophoresis) In response to suggestions from the initial review of this application, we have examined the possibility of using the distal denervated muscle itself as a delivery vehicle, and we now show that this is possible. The preliminary data in this revised application clearly show the feasibility of using the distal denervated muscle and/or nerve to effectively deliver exogenous compounds to an anatomically discrete set of Schwann cell tubes at a more proximal nerve repair site. Since the accuracy of motor neuron axon regeneration is largely determined by the Schwann cell tubes that an axon enters at the initial repair site, such anatomical targeting of specific exogenously applied compounds could have a significant impact on eventual regeneration accuracy. This innovative approach is a significant addition to current interventions that directly target the motor neuron cell body itself. We are seeking to shift clinical and research attention by highlighting the distal denervated muscle and nerve pathway as a selective delivery mechanism; if successful this technique could be rapidly translated into standard clinical practice. PUBLIC HEALTH RELEVANCE: In the general US population peripheral nerve injuries are common, accounting for approximately 5% of all patients admitted to Level I trauma centers. Since only 10% of adults will recover normal nerve function using state-of-the-art current techniques a better understanding of the underlying mechanisms that limit the accuracy of peripheral nerve regeneration could, in the long-term, reduce the overall financial burden on the US health care system associated with extensive nerve injuries.